Pharmacokinetics (ADME)

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam. Clinical Pharmacology & Therapeutics governs how a drug acts on the body (pharmacodynamics) and what the body does to the drug (pharmacokinetics — ADME: Absorption, Distribution, Metabolism, Excretion). Master six formulas: Clearance = (Dose × F) / AUC, Steady-state Css = (Dose × F)/(CL × τ), Loading dose = (Vd × Target)/F, Maintenance dose = (CL × Target × τ)/F, t½ = 0.693 × Vd / CL, and Cockcroft-Gault CrCl = [(140 − age) × wt(kg)] / [72 × SCr(μmol/L) ÷ 88.4] (×0.85 if female). Two high-yield hooks for the Saudi GP Board: ADRs split into Type A (predictable, dose-dependent) and Type B (idiosyncratic, immune-mediated), and rational prescribing follows the WHO 6-step Guide to Good Prescribing.

🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Pharmacokinetics (ADME)

Absorption depends on the drug’s physiochemistry and the route — oral bioavailability (F) is reduced by first-pass hepatic metabolism via CYP450 (notably CYP3A4, CYP2D6, CYP2C9). Distribution is quantified by volume of distribution (Vd): a high Vd (e.g., >10 L/kg for chloroquine) implies extensive tissue binding; a low Vd suggests retention in plasma (e.g., heparin). Metabolism converts lipophilic drugs into polar metabolites (Phase I — CYP450 oxidation/reduction; Phase II — glucuronidation, sulfation). Excretion is renal (glomerular filtration + tubular secretion) or biliary. Clearance (CL) is the volume of plasma cleared per unit time and underpins the steady-state equation above.

Pharmacodynamics

Drugs act on receptors: agonists produce maximum response, partial agonists show sub-maximal Emax even at full occupancy (e.g., buprenorphine), antagonists block agonist binding (competitive vs non-competitive). Potency = EC50; efficacy = Emax. The therapeutic index (TI = TD50/ED50) quantifies safety — a narrow TI drug (warfarin, digoxin, theophylline, aminoglycosides) mandates therapeutic drug monitoring (TDM).

Dosing Calculations

Loading dose rapidly achieves target plasma concentration — useful for drugs with long t½ (digoxin, amiodarone).
Maintenance dose keeps Css within the therapeutic window.
For renal-excreted drugs, reduce dose or extend interval as CrCl falls; the Cockcroft-Gault formula above is the SCFHS-recommended estimator. Renally-cleared staples requiring dose adjustment in primary care: metformin, enalapril, vancomycin, gentamicin, dabigatran.

ADRs & Interactions

Type A reactions are predictable, dose-related, and common (e.g., bleeding from warfarin, hypoglycaemia from insulin). Type B are unpredictable, often immunologic (e.g., Stevens-Johnson syndrome from allopurinol, anaphylaxis from penicillins). Pharmacokinetic interactions: enzyme inducers (rifampicin, carbamazepine, St John’s Wort, phenytoin) lower levels of co-prescribed substrates; inhibitors (cimetidine, fluconazole, macrolides, grapefruit juice) raise them — classically CYP3A4. Pharmacodynamic interactions: additivity (aspirin + warfarin → bleeding), antagonism (β-blocker + salbutamol).

Rational Prescribing & Stewardship

The WHO 6-step model: (1) define the problem, (2) specify therapeutic objective, (3) choose P-drug, (4) start treatment, (5) monitor efficacy/toxicity, (6) stop/switch. Antimicrobial stewardship in primary care applies right drug, right dose, right route, right duration, right time, deferring empirical therapy pending cultures where appropriate; the Saudi MoH/Ministry of Defence Health Services protocols push for shortest effective duration (e.g., 5 days for uncomplicated cystitis, 5–7 days for community-acquired pneumonia in stable patients).

🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Edge Cases & Special Populations

Pregnancy — FDA categories (legacy) and the newer Pregnancy/Lactation Labeling Rule (PLLR) replace A/B/C/D/X. Avoid isotretinoin, warfarin (1st trimester teratogenicity), ACE-Is, tetracyclines, valproate, methotrexate; safer antihypertensives are labetalol, nifedipine, methyldopa. Lactation — check milk-to-plasma ratio and infant exposure; avoid codeine (ultra-rapid metabolisers produce toxic morphine), ergot alkaloids. Elderly — apply Beers Criteria (AGS 2023 update) to flag PIMs: avoid long-acting benzodiazepines, anticholinergics (diphenhydramine, oxybutynin), first-generation antipsychotics for delirium. Start-low-go-slow; Vd of lipophilic drugs rises with body fat, while renal CL falls, prolonging t½.

Worked Example

A 70-year-old woman, 60 kg, SCr 150 μmol/L, requires gentamicin for Gram-negative sepsis. Target peak = 8 mg/L, τ = 24 h.

CrCl = [(140 − 70) × 60] / [72 × (150 ÷ 88.4)] = (4200) / [72 × 1.697] = 4200 / 122.2 ≈ 34 mL/min.
Assume Vd ≈ 0.25 L/kg × 60 = 15 L, CL ≈ 5 mL/min (reduced).
Loading dose = Vd × Target / F = 15 × 8 / 1 = 120 mg, then re-dose guided by TDM (random level at 8–12 h) — gentamicin is a narrow-TI drug.

Common Mistakes

Cockcroft-Gault: forgetting the ÷88.4 conversion when labs report μmol/L, or omitting the ×0.85 female factor.
Loading dose formula: forgetting F (relevant for oral drugs with low bioavailability such as digoxin ≈ 0.7).
Confusing potency (EC50) with efficacy (Emax) — a partial agonist has lower efficacy but can equal an antagonist’s apparent effect at higher doses.
Treating CYP450 induction (delayed onset — enzyme synthesis takes ~1 week) the same as inhibition (immediate).

Practice Prompts

A patient on simvastatin is prescribed clarithromycin. Predict the interaction, propose management, and identify two safer macrolides.
Estimate the maintenance dose of vancomycin for a 50 kg patient with CrCl 60 mL/min targeting an AUC₂₄/MIC of 400 mg·h/L, then state how you would monitor.

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Pharmacokinetics (ADME)